Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents With HIV

Epidemiology

Malaria continues to contribute disproportionately to the global burden of infectious diseases, especially in sub-Saharan Africa and Southeast Asia. In 2015, the World Health Organization estimated that 97 countries had ongoing malaria transmission, and almost half the world’s population, approximately 3.2 billion people, lived in areas with some risk of malaria transmission.¹ Of the nearly 214 million cases of malaria worldwide in 2015 (based on reports and models), approximately 88% (188 million) occurred in Africa, the area of the world with the highest HIV prevalence.¹ Approximately 438,000 deaths were attributable to malaria in 2015, with ~90% occurring in Africa and 74% of those deaths in children younger than 5 years of age. Fifteen countries, mainly in sub-Saharan Africa, account for 80% of malaria cases and 78% of deaths worldwide.¹ Current attributable morbidity and mortality are likely underestimated, given our limited understanding, surveillance, and reporting of non-falciparum infections.

Malaria typically is transmitted by the bite of an infected female Anopheles sp. mosquito. Reports of vertical transmission and infection after blood transfusion do exist, but these routes of transmission are uncommon in non-endemic areas.^2-5

Malaria in humans can be caused by any one of five species: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, and Plasmodium knowlesi (a zoonotic species that also infects macaques in Southeast Asia).⁴ Although P. vivax infections are more common and occur in a far wider geographic distribution,⁶ P. falciparum malaria represents the most serious public health problem because of its tendency toward severe or fatal infections. P. vivax, however, should not be discounted as a risk for travelers in many parts of the world.

Malaria and HIV both cause substantial morbidity and mortality, particularly in sub-Saharan Africa. Given this substantial overlap, even modest interactions between them have public health importance.^7,8 Malaria influences the natural history of HIV infection, and HIV infection alters the natural history and severity of malaria.⁹

Many foreign-born individuals develop malaria in the United States because of distant exposure before their arrival, or as a result of more recent travel for business or family reasons. Similarly, U.S.-born individuals can develop malaria during travel to endemic areas.^10-13 Failure to take appropriate chemoprophylaxis is a common problem for both groups of individuals.^14,15 People who formerly lived in malarious areas may believe that they are immune, and therefore do not need to take prophylaxis.¹⁶ Such patients are at high risk of infection, however, because they likely have lost partial immunity within 6 months after leaving endemic regions.

Consideration of malaria in returning travelers who are febrile is important: Of the nearly 50 million individuals who travel to developing countries each year, between 5% and 11% develop a fever during or after travel.^17-20 Malaria is a surprisingly common cause of these fevers.²¹

Clinical Manifestations

The clinical syndromes caused by Plasmodium species depend on prior exposure.²² While many native U.S. travelers have no prior immunity, clinical manifestations in those who have resided in malarious areas depend on whether they lived in an area with stable endemic malaria transmission (year round) or unstable (seasonal, infrequent or very low) transmission.²³

In stable endemic areas, children younger than age 5 years may experience chronic infections with recurrent parasitemia, resulting in severe anemia and death. Children who survive these infections usually acquire partial immunity by age 5 years, and if they remain in the area where malaria is endemic, they maintain this immunity into adulthood. In stable endemic areas, adults usually experience asymptomatic or milder infections as a result of this acquired immune response. However, as noted previously, patients who leave endemic areas and subsequently return may be at high risk of disease because they likely have lost partial immunity 6 months after leaving endemic regions.

In unstable transmission areas, protective immunity is not acquired. For populations in these areas, the overwhelming clinical manifestation is acute febrile disease that can be complicated by cerebral malaria, affecting persons of all ages.

When pregnant women in areas of unstable transmission develop acute malaria, the consequences may include spontaneous abortion and stillbirth. In more stable transmission areas, pregnant women, particularly primigravidas, may lose some acquired immunity. Although infections may continue to be asymptomatic, infected pregnant women may acquire placental malaria that contributes to intrauterine growth retardation, low birth weight, and increased infant mortality.

Patients with malaria can exhibit various symptoms and a broad spectrum of severity, depending upon factors such as the infecting species and level of acquired immunity in the host. HIV-immunosuppressed patients in endemic areas may lose acquired malarial immunity, and HIV-immunosuppressed adults with little or no previous malaria exposure (such as travelers) appear to be at increased risk of severe outcomes.²⁴

The incubation period for P. falciparum is from a week to several months, but most often less than 60 days. Patients can present much later (>1 year), but this pattern is more common with other species, especially P. vivax. In non-immune patients, typical symptoms of malaria include fever, chills, myalgias and arthralgias, headache, diarrhea, vomiting, and other non-specific signs. Splenomegaly, anemia, thrombocytopenia, pulmonary or renal dysfunction, and neurologic findings also may be present. Classically, paroxysmal fevers occur every 48 hours for P. falciparum, P. vivax, and P. ovale malaria; those with P. malariae occur every 72 hours. This classic presentation is highly variable, however, and may not be present. P. knowlesi, known to cause human infection in Southeast Asia in travelers to jungle/forested areas, is clinically indistinguishable from other species of malaria, and the overwhelming majority of patients present with uncomplicated disease (~90%).²⁵

Uncomplicated malaria infection can progress to severe disease or death within hours. Malaria with central nervous system symptoms can be particularly ominous. Cerebral malaria refers to unarousable coma not attributable to any other cause in patients infected with P. falciparum; in Africa, case fatality rates with cerebral malaria approach 40%.^26-28 The risk of severe and complicated illness is increased in patients with high levels of parasitemia and without partial immunity. Metabolic acidosis is an important manifestation of severe malaria and an indicator of poor prognosis.²⁹ Other acute complications include renal failure, hypoglycemia, disseminated intravascular coagulation, shock, and acute pulmonary edema.³⁰ P. falciparum is the species most commonly responsible for severe disease and death, although the other species can cause severe disease and death as well.^25,31

Effect of HIV on Parasitemia and Clinical Severity

HIV infection impairs acquired immunity to malaria that is present in older children and adults in stable endemic areas. Large cohort studies have demonstrated the increased frequency (with rates one- to two-fold higher) of both parasitemia and clinical malaria in HIV-infected adults, with increasing risk and higher-density parasitemia associated with more advanced immunosuppression, particularly among those with CD4 T‑lymphocyte (CD4) cell counts <350 cells/mm³.^32-34 Increased rates of malaria among individuals with HIV do not appear to be as great as the rates observed with classic opportunistic infections such as tuberculosis and Pneumocystis jirovecii pneumonia.³⁵

In a prospective cohort study in an area with unstable malaria transmission, HIV-infected non-immune adults were found to be at increased risk of severe malaria, and the risk was associated with a low CD4 cell count.³⁶ Non-immune HIV-infected patients were substantially more likely to have severe clinical malaria than were non-immune patients without HIV. In KwaZulu Natal, an area of unstable malaria transmission, HIV-infected adults hospitalized for malaria were substantially more likely to die or require an intensive care unit admission than those who were not HIV-infected.³⁷ In contrast, HIV infection did not confer an increased risk of poor outcomes among partially immune adults in areas with more stable transmission.³² In a cross-sectional study of travelers returning to France from malaria-endemic areas between 2000 and 2003, HIV-infected individuals with CD4 counts <350 cells/mm³ were at significantly higher risk of developing severe malaria, compared with those who were HIV-negative.³⁴

Effects of Malaria on Mother-to-Child HIV Transmission

Placental malaria also has been associated with increased expression of CCR5 receptors in placental macrophages³⁸ and increased viral load,³⁹ raising the possibility of placental malaria leading to increased mother-to-child transmission (MTCT) of HIV. In addition, fetal immune activation by malaria antigens may increase susceptibility to HIV infection.⁴⁰ Data are conflicting concerning the effect of malaria during pregnancy on risk of MTCT in the pre-ART era and are limited since the widespread use of ART for prevention of MTCT.^41-43

Diagnosis

A malaria diagnosis must be considered in all febrile patients who have traveled to or lived in malaria-endemic areas or who have received blood products, tissues, or organs from individuals who have been to such areas.

Several diagnostic methods are available, including microscopic diagnosis, antigen detection tests, polymerase chain reaction-based assays, and serologic tests, though serologic tests which detect host antibody are inappropriate for the diagnosis of acute malaria.

Direct microscopic examination of intracellular parasites on stained blood films is the standard for definitive diagnosis in nearly all settings because it allows for identification of the species and provides a measure of parasite density. Microscopic diagnosis of P. knowlesi is difficult because it is commonly misidentified as P. malariae, which tends to follow a more benign course. Providers should have a high index of suspicion for P. knowlesi in travelers returning from Southeast Asia.³¹

In non-immune patients with all types of malaria, symptoms may develop before detectable levels of parasitemia are evident. For this reason, several blood smear examinations taken at 12- to 24-hour intervals may be needed to positively rule out a diagnosis of malaria in symptomatic patients. Guidelines for laboratory diagnosis are summarized elsewhere and are available at the Centers for Disease Control and Prevention (CDC)’s malaria website (https://www.cdc.gov/malaria). Rapid diagnostic tests, particularly for the diagnosis of P. falciparum, can be used depending on the local expertise and practice and can facilitate prompt diagnosis and treatment of infected patients, but must be followed by microscopy.

Preventing Exposure

Pre-travel evaluation by a travel medicine specialist can provide specific education about risk of exposure in various geographic locales, the utility of insecticide-impregnated bed nets in the setting where the individual will be traveling or residing, and the use of DEET (N,N-diethyl-3-methyl-benzamide)-containing repellants.

Infection with P. falciparum can be more severe in HIV-infected patients with low CD4 cell counts and in pregnant women regardless of HIV infection than in other individuals. Because no chemoprophylactic regimen is completely effective, HIV-infected patients with low CD4 cell counts and women who are pregnant or likely to become pregnant should be advised to avoid travel to areas with malaria transmission if possible (AIII). If travel to an endemic area cannot be deferred, use of an effective chemoprophylaxis regimen is essential, along with careful attention to personal protective measures to prevent mosquito bites.

Preventing Disease

For United States travelers (including HIV-infected patients) to endemic areas, a combination of chemoprophylaxis and personal protective measures can be highly effective in preventing malaria. Recommendations for prophylaxis are the same for HIV-infected patients as for those who are not HIV-infected and are available at CDC’s malaria website (AIII) (https://www.cdc.gov/malaria).

Malaria incidence has been markedly reduced in African adults with HIV who receive cotrimoxazole (trimethoprim-sulfamethoxazole) prophylaxis.⁴⁴ A recent study of HIV-infected patients in Uganda demonstrated that malaria burden was reduced by 70% with cotrimoxazole, and then reduced another 50% when antiretroviral (ARV) drugs were provided, and finally reduced another 50% with provision of insecticide-treated nets.⁴⁵ However, cotrimoxazole is not as effective an antimalarial prophylactic regimen as the recommended antimalarials. Therefore, HIV-infected travelers should not rely on prophylaxis with cotrimoxazole for chemoprophylaxis against malaria (AIII).

Treating Disease

Because P. falciparum malaria can progress within hours from mild symptoms or low-grade fever to severe disease or death, all HIV-infected patients with confirmed or suspected P. falciparum infections should be admitted to the hospital for evaluation, initiation of treatment, and observation of response to treatment (AIII). Diagnosis prior to treatment should always be pursued; however, treatment should not be delayed when malaria is strongly suspected but laboratory services are unavailable or results will be delayed (AIII).

Choice of treatment is guided by the degree of parasitemia, the species of Plasmodium, a patient’s clinical status, and the likely drug susceptibility of the infecting species (as determined by where the infection was acquired).

For HIV-infected patients who do acquire Plasmodium infection, treatment recommendations are the same as for HIV-uninfected patients (AIII). CDC posts current treatment recommendations on its website (https://www.cdc.gov/malaria) and has clinicians on call 24 hours to provide advice to clinicians on diagnosing and treating malaria (CDC Malaria Hotline: (770) 488-7788; Monday through Friday. 8 a.m. to 4:30 p.m. EST. (770) 488-7100 after hours).

Special Considerations with Regard to Starting Antiretroviral Therapy (ART)

There is no reason to defer ART initiation after patients have recovered from acute malaria.

Monitoring of Response to Therapy and Adverse Events (Including IRIS)

Careful monitoring of patients (especially those with P. falciparum malaria) is necessary, including measurement of peripheral parasitemia and hemoglobin and blood glucose levels, as well as assessment of cerebral, pulmonary, and renal function. Frequency of monitoring depends on severity of disease, a patient’s immune status, and the species of Plasmodium.

Chemoprophylaxis or treatment for malaria in patients receiving ARV agents requires attention to potential drug interactions. Several potential drug interactions can occur between antimalarial and HIV drugs as well as other medications used to treat HIV-associated opportunistic infections (see Table 4).⁴⁶ Providers are also encouraged to check for drug-drug interactions by using an interactive web-based resource from the University of Liverpool at https://www.hiv-druginteractions.org. Mefloquine in repeated doses has been observed to reduce area under the concentration-time curve and maximal plasma concentrations of ritonavir by 31% and 36%, respectively. Insufficient data are available to suggest that dose adjustments are needed.

Quinine levels may be increased by ritonavir-containing regimens or cobicistat; conversely, nevirapine and efavirenz can reduce plasma quinine levels. Potential interactions can occur between ritonavir or cobicistat and chloroquine, but their clinical significance is unclear, and until further data are available, no dose adjustments are recommended.

Artemether-lumefantrine is now approved in the United States for treatment of uncomplicated P. falciparum infection. Data in children suggest that this combination is well tolerated and safe in HIV-infected children,⁴⁷ however, efficacy data are conflicting in HIV-infected adults. An open-label trial in Tanzania demonstrated excellent efficacy (97.6%) of artemether-lumefantrine for treating uncomplicated P. falciparum malaria in HIV‑infected adults on nevirapine-based ART.⁴⁸ Conversely, 28-day clinical and parasitologic response was sub‑optimal in the efavirenz-based ART group, with efficacy of 82.5%, and a 19-fold increased risk of recurrent parasitemia compared to the control group of HIV-infected adults not on ART.⁴⁸ Artesunate is available for treatment of severe malaria through a compassionate use Investigational New Drug application. A trial in Uganda demonstrated the effectiveness of artesunate plus amodiaquine in HIV-infected children, but treatment was associated with increased risk of neutropenia in those on ART, particularly zidovudine, which was attributed to the amodiaquine component of therapy.⁴⁹

Ritonavir or cobicistat-boosted ARV regimens and non-nucleoside reverse transcriptase inhibitors have the potential to affect metabolism of artemisinin-containing drugs,⁵⁰ but the overall effect and clinical significance remain unclear. No dose alterations currently are recommended.

No immune reconstitution inflammatory syndrome (IRIS) has been described in association with malaria.

Managing Treatment Failure

HIV-infected individuals are at increased risk of malaria treatment failure.⁵¹ Management of treatment failure is the same in HIV-infected and HIV-uninfected patients, except for considerations about drug interactions between ART and antimalarial drugs. Drug-resistant malaria and possible concomitant infections should be considered in HIV-infected patients whose malaria fails to respond to therapy.

Preventing Recurrence

If the species of malaria identified is P. vivax or P. ovale, which can cause recurrence due to hepatic phase of infection, then treatment with primaquine in addition to standard treatment is recommended to prevent recurrence (AI). Guidelines for primaquine treatment do not differ in HIV-infected individuals.

Special Considerations During Pregnancy

Malaria in pregnancy affects both mother and fetus. Infection with P. falciparum during pregnancy can increase maternal risk of severe disease and anemia and risk for stillbirth, preterm birth, and low birth weight.⁵² The diagnosis of malaria in pregnant women is the same as in women who are not pregnant.

For pregnant women with a diagnosis of uncomplicated malaria caused by P. malariae, P. ovale, chloroquine-sensitive P. vivax, and chloroquine-sensitive P. falciparum, prompt treatment with chloroquine is recommended.⁵³ For pregnant women with a diagnosis of chloroquine-resistant P. vivax, treatment with mefloquine for 7 days is recommended. For pregnant women with a diagnosis of uncomplicated chloroquine-resistant P. falciparum malaria, prompt treatment with mefloquine or quinine and clindamycin is recommended as per CDC guidelines.⁵⁴

On the basis of extensive experience with its use, chloroquine is considered the drug of choice for prophylaxis and treatment of sensitive strains of malaria in pregnancy. Although quinine at high doses has been associated with an increased risk of birth defects (especially deafness) in some animal species and humans (usually during attempted abortion), use of therapeutic doses in pregnancy is considered safe.^53,55 Because of the potential for hypoglycemia, glucose levels should be monitored in pregnant women treated with quinine and their neonates. Clindamycin use has not been associated with birth defects. Animal and human data on use of prophylactic and treatment doses of mefloquine do not suggest teratogenicity and the drug can be used safely during all trimesters.⁵⁶ One randomized trial of mefloquine used in addition to daily cotrimoxazole for malaria prophylaxis in pregnant women living with HIV demonstrated an increased risk of transmission of HIV to the infant in the mefloquine arm, potentially because of drug interactions.⁵⁷ Although experience is limited, available data on artemether-lumefantrine during pregnancy suggest that use is not associated with increased adverse events or birth defects.⁵⁸ A pharmacokinetic study in HIV-uninfected persons found no difference in levels between pregnant and non-pregnant subjects except for small differences in elimination half-life of lumefantrine.⁵⁹ Data on pharmacokinetics in HIV-infected pregnant women were not included. Because of limited data, atovaquone-proguanil is not recommended for treatment in pregnancy and should be used only if quinine plus clindamycin, quinine monotherapy, or mefloquine are unavailable or not tolerated.⁵⁵ Tetracyclines are not recommended in pregnancy because of increased risk of maternal hepatotoxicity and staining of fetal teeth and bones. Primaquine use during pregnancy is not recommended because of limited experience with its use and the potential for fetal glucose-6-phosphate dehydrogenase (G6PD) deficiency. After treatment, all pregnant women with P. vivax and P. ovale should receive chloroquine prophylaxis for the duration of pregnancy to avoid relapses. Once-weekly mefloquine can be used for prophylaxis in pregnant women with P. vivax acquired in an area with chloroquine-resistant strains. Women who have normal G6PD screening tests can be treated with primaquine after delivery.

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